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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complement activation products are known to be generated in the setting of both experimental and human sepsis. C5 activation products (C5a anaphylatoxin and the membrane attack complex [MAC] C5b-9) are generated during sepsis following infusion of endotoxin, or after cecal ligation and puncture (CLP), which produces polymicrobial sepsis. C5a reacts with its receptors C5aR and C5L2 in a manner that creates the "cytokine storm", and is associated with development of multiorgan failure (MOF). A number of other complications arising from the interaction of C5a with its receptors include apoptosis of lymphoid cells, loss of innate immune functions of neutrophils (PMNs, polymorphonuclear leukocytes), cardiomyopathy, disseminated intravascular coagulation, and complications associated with MOF. Neutralization of C5a in vivo or absence/blockade of C5a receptors greatly reduces the adverse events in the setting of sepsis, markedly attenuates MOF, and greatly improves survival. Regarding the possible role of C5b-9 in sepsis, the literature is conflicting. Some studies suggest that C5b-9 is protective, while other studies suggest the contrary. Clearly, in human sepsis, C5a and its receptors may be logical targets for interception.
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PMID:Role of C5 activation products in sepsis. 2117 Apr 90

Invasive meningococcal disease is a world wide challenge. Most cases occur in immunocompetent children and young adults, but some immunodeficiencies are linked to a greater risk of invasive neisserial infections. One of these is complement component deficiencies, particularly deficiency of properdin and the terminal complement components. We describe a case of recurrent meningococcal sepsis in a young man who was later diagnosed with complete lack of complement component C5. This case report emphasizes the need of having complement deficiencies in mind when being introduced to patients with invasive Neisseria-infections.
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PMID:Recurrent meningococcal sepsis in a presumptive immunocompetent host shown to be complement C5 deficient-a case report. 2163 55

There is abundant evidence that infectious sepsis both in humans and mice with polymicrobial sepsis results in robust activation of complement. Major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2) and, perhaps, the terminal complement activation product, C5b-9. These products (and others) also cause dysfunction of the innate immune system, with exaggerated early proinflammatory responses, followed by decline of the innate immune system, leading to immunosuppression and multiorgan dysfunction. Generation of C5a during sepsis also leads to activation of neutrophils and macrophages and ultimate appearance of extracellular histones, which have powerful proinflammatory and prothrombotic activities. The distal complement activation product, C5b-9, triggers intracellular Ca fluxes in epithelial and endothelial cells. Histones activate the NLRP3 inflammasome, products of which can damage cells. C5a also activates MAPKs and Akt signaling pathways in cardiomyocytes, causing buildup of [Ca]i, defective action potentials and substantial cell dysfunction, resulting in cardiac and other organ dysfunction. Cardiac dysfunction can be quantitated by ECHO-Doppler parameters. In vivo interventions that block these complement-dependent products responsible for organ dysfunction in sepsis reduce the intensity of sepsis. The obvious targets in sepsis are C5a and its receptors, histones, and perhaps the MAPK pathways. Blockade of C5 has been considered in sepsis, but the FDA-approved antibody (eculizumab) is known to compromise defenses against neisseria and pneumonococcal bacteria, and requires immunization before the mAb to C5 can be used clinically. Small molecular blocking agents for C5aRs are currently in development and may be therapeutically effective for treatment of sepsis.
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PMID:Complement as a Major Inducer of Harmful Events in Infectious Sepsis. 3218 6

Neutrophils are the most abundant innate cell population and a key immune player against invading pathogens. Neutrophils can kill both bacterium and spores of Bacillus anthracis, the causative anthrax pathogen. Unlike interactions with professional phagocytes, the molecular recognition of anthrax by neutrophils is largely unknown. In this study, we investigated the role of complement C3 deposition on anthrax particles for neutrophil recognition of bacterium and/or its cell wall peptidoglycan, an abundant pathogen-associated molecular pattern that supports anthrax sepsis. C3 opsonization and recognition by complement receptors accounted for 70-80% of the affinity interactions between neutrophils and anthrax particles at subphysiologic temperatures. In contrast, C3 supported up to 50% of the anthrax particle ingestion under thermophysiologic conditions. Opsonin-dependent low affinity interactions and, to a lower extent, opsonin-independent mechanisms, provide alternative entry routes. Similarly, C3 supported 58% of peptidoglycan-induced degranulation and, to a lower extent, 23% of bacterium-induced degranulation. Interestingly, an opsonin independent mechanism mediated by complement C5, likely through C5a anaphylatoxin, primes azurophilic granules in response to anthrax particles. Overall, we show that C3 deposition supports anthrax recognition by neutrophils but is dispensable for pathogen ingestion and neutrophil degranulation, highlighting immune recognition redundancies that minimize the risk of pathogen evasion.
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PMID:C3 Opsonization of Anthrax Bacterium and Peptidoglycan Supports Recognition and Activation of Neutrophils. 3266 3